Necrotic myelopathy (myelomalacia) in rats with allergic encephalomyelitis treated with tilorone. (1/32)

Necrosis of the spinal cord was produced by administering tilorone to rats before or during the incubation period of experimental allergic encephalomyelitis (EAE). Under slected conditions of dose and timing, the drug delayed onset of clinical signs but did not prevent progression to paralysis. The lymphocytic component of the inflammatory lesions was reduced, but this was accompanied by a dramatic increase of monocytes in the spinal cord, followed by softening (myelomalacia). This new variant of EAE simulates necrotic myelopathy in man. The similarity provides support for an autoimmune etiology of the latter. Furthermore, the inverse relation between lymphocytic cuffs around vessels and massive monocytic infiltration of the cord adds to the growing evidence that lymphocytic cuffs protect the neural parenchyma by "vascular blockade."  (+info)

In vivo and in vitro stimulation of mouse spleen leukocytes by BL-20803, a low-molecular-weight interferon inducer. (2/32)

BL-20803, a low-molecular-weight compound, although able to elicit circulating interferon in the mouse, failed to protect cultured cell lines in vitro from infection by interferon-sensitive viruses. Of the tissues analyzed for interferon content after oral administration of the drug to mice, spleen and lung contained the largest amounts of the virus inhibitor. Spleen cells from such dosed animals when isolated into in vitro cultures elaborated small amounts of interferon into the culture medium. The time sequence of acquisition by spleen cells of the ability to produce interferon closely correlated with the kinetics of development of the circulating interferon response in the intact mouse. When spleen cells were separated on the basis of adherence or nonadherence to a plastic surface, the bulk of the interferon activity was found to be associated with the adherent cells. Upon exposure to BL-20803 in cell culture, adherent cells and, to a lesser extent, nonadherent cells from untreated mice were stimulated to produce interferon-like activity. The biological behavior of BL-20803 is shown to have striking similarities with that of the structurally different low-molecular-weight inducer tilorone hydrochloride.  (+info)

NK cells mediate increase of phagocytic activity but not of proinflammatory cytokine (interleukin-6 [IL-6], tumor necrosis factor alpha, and IL-12) production elicited in splenic macrophages by tilorone treatment of mice during acute systemic candidiasis. (3/32)

The participation of NK cells in the activation of splenic macrophages or in resistance to systemic candidiasis is still a matter of debate. We had previously reported that there is a correlation between natural killer cell activation and resistance to systemic candidiasis. In those experiments we had used tilorone to boost NK cell activity in mice. Here we show a mechanism elicited by tilorone in splenic macrophages which could explain their effect on mouse survival during acute disseminated Candida albicans infection. The results demonstrate that tilorone treatment elicits, by a direct effect, the production of proinflammatory cytokines (interleukin-6 [IL-6], tumor necrosis factor alpha [TNF-alpha], and IL-12) by splenic macrophages. In addition, it increases the capacity of splenic macrophages to phagocytize C. albicans through activation of NK cells. We also demonstrate that the presence of NK cells is essential for maintaining a basal level of phagocytic activity, which characterizes splenic macrophages of naive control mice. The results demonstrate that it is possible to identify two phenotypically and functionally peculiar cell populations among splenic macrophages: (i). cells of the "stimulator/secretor phenotype," which show high levels of major histocompatibility complex (MHC) class II surface expression, are poorly phagocytic, and synthesize the proinflammatory cytokines IL-6, TNF-alpha, and IL-12, and (ii). cells of the "phagocytic phenotype," which express low levels of MHC class II molecules, are highly phagocytic, and do not secrete proinflammatory cytokines.  (+info)

Effect of tilorone treatment on intracellular microbial infections in specific-pathogen-free mice. (4/32)

Specific-pathogen-free CD-1 mice were treated orally with the drug tilorone (2,7-bis[2-diethylaminoethoxy]fluoren-9-one hydrochloride) at dosages of 10 or 100 mg per kg of body weight. Drug was given 24 h before challenge and then every other day for up to 15 days. Growth of sublethal doses of Listeria monocytogenes, Mycobacterium bovis (BCG Montreal), M. tuberculosis H37Rv, and Salmonella enteritidis in the livers and spleens of intravenously challenged mice was significantly increased compared with that in control animals receiving distilled water orally. Tilorone given every other day at a dosage of 10 mg/kg reduced (but did not completely ablate) the tuberculin response to the mycobacterial infections. Both tuberculin hypersensitivity and anti-mycobacterial resistance returned to normal values within days of stopping the drug treatment. Tilorone treatment at the 100-mg/kg dose level increased the growth of S. enteritidis in both intravenously and intragastrically challenged mice; this effect seemed to be due to the reduced ability of the host to express the normal granulomatous response to the microbial infection within the liver and spleen.  (+info)

Inhibition of herpesvirus deoxyribonucleic acid and protein synthesis by tilorone hydrochloride. (5/32)

Tilorone hydrochloride at a concentration of 10 mug/ml very efficiently inhibited herpes simplex virus growth in BSC1 cells when the virus is infected at a low multiplicity of infection. The adsorption of the virus was not affected by the drug, and the penetration of the deoxyribonucleic acid of the input virus into the cytoplasm and nuclei proceeded normally when tilorone hydrochloride was present. However, newly synthesized viral deoxyribonucleic acid was not detectable under these conditions, there was a remarkable decrease in the rate of viral polypeptide synthesis, and virus particles were not formed. The inhibition of herpesvirus growth by tilorone hydrochloride was absolutely dependent on the presence of the drug in the cultures. Pretreatment of the cells with the drug did not result in resistance to herpesvirus infection after the removal of the drug.  (+info)

The effect of tilorone hydrochloride on the growth of several animal viruses in tissue cultures. (6/32)

Tilorone hydrochloride, at a concentration of 10 mug/ml inhibits the growth of herpes simplex virus type 1 in BS-C-1 cells. The growth of vaccinia virus in BS-C-1 cells is partially inhibited; however, six viruses containing RNA, including four members of the togavirus group grown in chick fibroblasts, are not affected by the drug. The inhibition of the growth of herpes virus by tilorone hydrochloride is greater when the multiplicity of infection is lower than 1 p.f.u/cell and when the drug is added early in the course of infection.  (+info)

alpha7 nicotinic acetylcholine receptor agonist properties of tilorone and related tricyclic analogues. (7/32)

BACKGROUND AND PURPOSE: The alpha7 nicotinic acetylcholine receptor (nAChR) has attracted considerable interest as a target for cognitive enhancement in schizophrenia and Alzheimer's Disease. However, most recently described alpha7 agonists are derived from the quinuclidine structural class. Alternatively, the present study identifies tilorone as a novel alpha7-selective agonist and characterizes analogues developed from this lead. EXPERIMENTAL APPROACH: Activity and selectivity were determined from rat brain alpha7 and alpha4beta2 nAChR binding, recombinant nAChR activation, and native alpha7 nAChR mediated stimulation of ERK1/2 phosphorylation in PC12 cells. KEY RESULTS: Tilorone bound alpha7 nAChR (IC(50) 110 nM) with high selectivity relative to alpha4beta2 (IC(50) 70 000 nM), activated human alpha7 nAChR with an EC(50) value of 2.5 microM and maximal response of 67% relative to acetylcholine, and showed little agonist effect at human alpha3beta4 or alpha4beta2 nAChRs. However, the rat alpha7 nAChR maximal response was only 34%. Lead optimization led to 2-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-xanthen-9-one (A-844606) with improved binding (alpha7 IC(50) 11 nM, alpha4beta2 IC(50)>30 000 nM) and activity at both human and rat alpha7 nAChR (EC(50)s 1.4 and 2.2 microM and apparent efficacies 61 and 63%, respectively). These compounds also activated native alpha7 nAChR, stimulating ERK1/2 phosphorylation in PC12 cells. CONCLUSIONS AND IMPLICATIONS: Tilorone, known as an interferon inducer, is a selective alpha7 nAChR agonist, suggesting utility of the fluorenone pharmacophore for the development of alpha7 nAChR selective agonists. Whether alpha7 stimulation mediates interferon induction, or whether interferon induction may influence the potential anti-inflammatory properties of alpha7 nAChR agonists remains to be elucidated.  (+info)

Pharmacokinetics of a synthetic interferon inducer amixin in mice. (8/32)

Pharmacokinetics of amixin, a synthetic interferon inducer, has been studied in mice under intravenous and oral routes of administration. Following oral administration, 80% of the drug was eliminated in the unchanged form. Its absolute biological availability comprised 0.7. In comparison to oral administration, after intravenous injection concentrations of amixin and its radioactive metabolites were higher during the first 5-120 min of the experiment in all organs and tissues. During the first 4-24 h, we observed an increase in the total radioactive material that was similar for both modes of administration. Low drug elimination rate was noted under both conditions. A novel integral model-independent method for estimation of equilibrium tissue-to-plasma partition ratios (K(p) has been proposed. The suggested integral parameter K(p) does not depend on the structure of the kinetic scheme and, most importantly, could be used for analysis of incomplete kinetic curves. We also propose a combined model that could help determine parameters of irreversible xenobiotic binding, the extent of the absorption from the intestine and relative efficacy of the hepatic excretion, in particular presystemic drug elimination.  (+info)

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